tbuckley/cabot-search huggingface dataset:
DDEL-01. The role of key pharmacodynamic and pharmacokinetic parameters in drug response prediction of pediatric tumors in the precision oncology study INFORM
Authors: Nora Jamaladdin, Heike Peterziel, Dina ElHarouni, Natalie Jäger, Tim Holland-Letz, Annette Kopp-Schneider, Romain Sigaud, Olaf Witt, Ina Oehme, Till Milde
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: The INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study is a European pediatric precision oncology program. Using state of the art molecular assays, INFORM aims for identification of targetable genetic alterations, matching drugs and clinical trials. High evidence targets were associated with doubling of progression free survival when patients received a matching drug. However, the fraction of tumors with high evidence drug targets remains low requiring functional layers of information such as drug sensitivity profiling. The aim of this project is to identify and investigate the role of key pharmacodynamic and pharmacokinetic parameters to improve the predictivity of ex vivo drug response of pediatric tumors. METHODS: Positive control cell lines harboring specific mutations (n=7) and primary tumors (n=121) from INFORM, including 10% ependymomas, 7% high grade gliomas, 5% neuroblastomas and 4% medulloblastomas, were profiled ex vivo using a library of n=76 clinically relevant oncology drugs in a 384 well plate format. Metabolic activity was measured after 72h of treatment. Quality control (QC) was done using the robust z-factor, correlation of replicates and mean negative control. Hit selection was based on maximum percentage inhibition, normalized AUC metric (DSSasym) and maximum serum concentration (Cmax) of the drug. Clinical follow-up was collected using a questionnaire. RESULTS: A linear mixed model revealed the DSSasym to be the strongest pharmacodynamic parameter in drug prediction in cell lines. Drug screens of n=105 INFORM cases passed QC. Application of the filtering parameters resulted in prediction of n=1-16 drugs/case (min-max). A data base of published pediatric pharmacokinetic parameters of the drug library was generated. Analysis of predictive parameters and clinical follow-up of clinical samples is ongoing. CONCLUSION: Including pharmacodynamic as well as clinical pharmacokinetic parameters is paramount to identify potentially clinically active compounds from ex vivo drug screen data. Further algorithm development is warranted.
Predictors of overall survival among Black South African men treated with androgen-deprivation therapy for metastatic prostate cancer.
Authors: Yoanna S Pumpalova, Adarsh Ramakrishnan, Shauli Minkowitz, Sean Doherty, Elvira Singh, Audrey Pentz, Wenlong Carl Chen, Alfred I. Neugut, Timothy Rebbeck, Maureen Joffe
Journal: Journal of Clinical Oncology (2022)

5046 Background: Men in sub-Saharan Africa (SSA) are disproportionately affected by prostate cancer (PCa), and many have metastatic disease (mPCA) at presentation. In SSA, androgen deprivation therapy (ADT) is the first-line treatment for mPCa, and often the only available therapy. Treatment failure and death is common. We identified predictors of overall survival (OS) in Black South African (SA) men with mPCa on ADT. Methods: We performed a retrospective analysis of prospectively gathered data from men diagnosed with mPCA (3/22/2016 - 10/30/2020) at Chris Hani Baragwanath Hospital in Johannesburg, which was also a study site for the concurrent Men of African Descent and Carcinoma of the Prostate study. We included men with mPCA treated with ADT (received at least 1 dose of luteinizing hormone-releasing hormone agonist and/or had surgical castration), who had ≥1 PSA level drawn ≥12 weeks after ADT start. OS was defined from ADT start to death. PSA progression (PSA-P) definition was adapted from PCWG 3. Cox regression models were used to identify predictors of OS. PSA-P was treated as a time-dependent covariate. Results: Of 200 men with mPCa, we excluded 6 who did not receive ADT and 41 without sufficient data for PSA-P analysis. Of 153 men, 26.8% were &lt;65 years old and 12% had a family history of PCa. Median PSA at diagnosis was 71.5 ng/mL (interquartile range (IQR) 20.7-432.6), median alkaline phosphatase level (ALP) 108 IU/L (79-224) and median hemoglobin (Hb) 13 g/dL (IQR 10-15). Median PSA nadir was 2.8 ng/mL (IQR 0.55-17.93). The rate of PSA-P at 1- and 2-years was 12.1% [95%CI 5.9-17.8] and 37.5% [95%CI 26.1-47.2]. The median follow-up was 2.75 years, and the 3-year OS was 61.9% [95%CI 52.7-72.6]. Cox proportional hazard ratio (HR) models of risk factors for OS are shown in Table 1. PSA-P was a strong predictor of OS. Men with PSA nadir &gt;4ng/mL after ADT start had a HR for death of 3.77 [1.86-7.62]. Men with ALP &gt;150 IU/L and those with Hb &lt;13.5g/dL at diagnosis were also at higher risk for death (HR 3.09 [1.64-5.83] and HR 2.00 [1.28-6.56] respectively). Conclusions: Among Black men in SA treated with ADT for mPCA, PSA-P strongly predicts OS. In this cohort, high ALP and anemia at diagnosis, and PSA nadir &gt;4ng/mL after ADT start are associated with higher risk for death. These factors can be used identify high risk men with mPCA, for whom early treatment escalation to chemotherapy should be considered. [Table: see text]
Mechanisms of thrombosis pathogenesis and prevention vary in patients with ovarian and endometrial cancers.
Authors: Irina V. Kaplieva, Ekaterina V. Verenikina, Elena M. Frantsiyants, Tatiana Yu. Myagkova, Yulia A. Pogorelova, Ekaterina I. Surikova, Elena A. Sheiko, Lidia K. Trepitaki, Nailya K. Guskova, Viktoria R. Zakharchenko, Marina A. Gusareva, Dmitriy P. Atmachidi, Pavel V. Chernogorov, Tatiana I. Moiseenko, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e17554 Background: Thrombosis in patients with gynecologic cancers worsens the outcome of antitumor treatment and is one of the leading causes of their death. The kallikrein-kinin system (KKS) is involved in both the regulation of thrombus formation and the development of cancer. The purpose of this study was to analyze characteristics of the KKS components in the blood in patients with endometrial cancer (EM) and ovarian cancer (OC) with and without secondary thrombosis (VTEC). Methods: The study included 39 patients, mean age 58.0±4.2 years: main groups – patients with OC T1c-3cN0M0 (n = 10) or EC T1a-2N0M0 (n = 9) with VTEC; comparison groups - patients with OC (n = 10) or EC (n = 10) without VTEC. EC was represented by adenocarcinomas (G1-G3), OC by serous carcinomas (90%) and clear cell adenocarcinomas (10%). The control group included healthy women of the corresponding age (n = 10). Blood levels of kallikrein 1 (K1), kallikrein 14 (K14), and kininogen (KG) were measured by ELISA after the surgery. Results: EC patients with VTEC showed 1.5 times (p &lt; 0.05) higher blood levels of K1, compared to donors, while other indices were unchanged. EC patients without VTEC had 4 times lower KG levels, compared to donors and EC+VTEC. In OC, regardless of the presence or absence of VTEC, levels of K1 in the blood increased, as well as in women with EC+VTEC, by 1.5 times (p &lt; 0.05) compared with donors, which was combined with a twofold increase in KG in OC+VTEC and a decrease in KG by 1.4 times in OC patients without VTEC. Blood levels of K14 increased only in OC patients without VTEC by an average of 1.9 times (p &lt; 0.05) compared with donors and OC+VTEC. Conclusions: The revealed changes in some KKS components in the blood demonstrate the similarity (K1 increase) and differences (KG increase only in OC) in the pathogenesis of thrombosis associated with gynecologic cancers. The mechanisms of protection against VTEC in the early postoperative period also showed common (KG decrease) and specific features associated with the characteristics of cancer (K14increase only in OC). The development of therapy aimed at correcting the identified disorders will allow an antitumor treatment program for this category of patients with maximum efficiency improving their quality of life and survival.
Systematic assessment of tumor mutational burden calculation across different sequencing platforms and cancer types and its implication in clinical decision-making.
Authors: Daqiang Sun, Hongzhen Tang, Haitao Luo
Journal: Journal of Clinical Oncology (2022)

2631 Background: Tumor mutation burden (TMB) has been validated as a biomarker to predict the response of immune checkpoint inhibitors (ICIs) treatment in various cancers. However, the effects of different sequencing platforms, cancer types and calculation methods on TMB as well as its cut-off value for predicting immunotherapy efficacy are still need to be further investigated. Methods: 4140 tumor samples were performed with targeted panel sequencing or whole exome sequencing (WES) in different platforms such as illumina and MGI. Public sequencing data from 3680 samples which contained targeted panel sequencing, WES and whole genome sequencing were obtained. The impact of different sequencing platforms, sequencing methods and calculation methods on the calculation of TMB were assessed. Further, targeted panel sequencing data from 71 sample of lung cancer patients treated with ICIs were used to determine the best cut-off value of TMB for predicting immunotherapy response. Results: TMB values calculated by different platforms and different sequencing methods were similar and there was no significant difference. The distribution of TMB at different sequencing depths and tumor purity were analyzed. We found that there was no significant difference in the distribution of TMB when the sequencing depth was greater than 500´, the HE purity was greater than 0.1 or NGS purity was greater than 0.3. In addition, the correlation of TMB calculated from single-sample and paired-sample is 0.95. Further, the optimal cut-off value of TMB in lung cancer treated with ICIs was determined to be 8 through ROC curve analysis, and patients with TMB ≥ 8 had better outcomes than patients with TMB &lt; 8. Conclusions: This study systematically analyzed the factors which influenced the TMB calculation, and verifies the feasibility of TMB calculation from single-sample. More importantly, the cut-off value of TMB for predicting immunotherapy efficacy in lung cancer was defined as 8 in East Asian populations, which can help in clinical decision-making.
MEDB-15. Dynamic chromatin alteration induces oncogenic hijacking by essential transcriptional factors during SHH medulloblastoma tumorigenesis
Authors: Ryo Shiraishi, Gabriele Cancila, Kohei Kumegawa, Patricia da Silva, Owen Chapman, Wang Wanchen, Maki Jami, Mikio Hoshino, Stefan Pfister, Lukas Chavez, Reo Maruyama, Olivier Ayrault, Daisuke Kawauchi
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is a malignant brain tumor that occurs in the cerebellum, most frequently in children. Medulloblastoma is molecularly classified into four major groups, and therapies are now being developed according to the nature of these groups and subgroups. However, there are currently no effective molecularly targeted drugs for most of these groups. In recent years, we have been analyzing the genomes of medulloblastomas to identify genetic mutations involved in tumorigenesis. Among them, mutations in chromatin modifiers are frequently detected in medulloblastoma, suggesting the importance of alterations in the epigenome in tumor development. However, it remains unclear how epigenomic changes are involved in tumorigenesis. Here, we have used the SHH-group medulloblastoma (MB-SHH) mouse model to understand the epigenomic changes during tumor development and identify new therapeutic targets for medulloblastoma. To this end, we utilized an Atoh1-EGFP:Ptch1+/- mice that specifically label cerebellar granule cell progenitors (GNPs) that are known to be the cellular origin of MB-SHH, preneoplastic (PNCs) and tumor cells with EGFP during MB-SHH formation. Following FACS-based collection of EGFP-positive cells, comparative ATAC-seq analysis revealed that the open chromatin regions dynamically changed during transformation of GNPs into PNCs with enrichment of nuclear factor I (NFI) binding motifs. Cut &amp; Tag analysis on these cells showed that NFI proteins bound chromatin regions that become more accessible during tumorigenesis, suggesting that NFI could play an important role in tumorigenesis after the epigenomic changes. Indeed, CRISPR-engineered in vivo somatic deletion of Nfia and/or Nfib prevented hyperplasia formation, confirming their essential role in tumor initiation. Knockdown of either NFIA or NFIB in patient-derived xenograft models also attenuated tumor growth. Thus, our study has uncovered a novel oncogenic mechanism that contributes to the development of MB-SHH tumors via alterations of accessible chromatin and aberrant DNA binding of NFI transcription factors.
Review of health care access duration among cancer patients at a large health plan.
Authors: Wilbur Rutter, William Cavers, Shivaani Prakash, Elisea Avalos-Reyes, Kjel Andrew Johnson
Journal: Journal of Clinical Oncology (2022)

e18758 Background: Cancer patients have unique, long-term health care needs and access to timely and affordable care is essential. Little is known about cancer patients’ propensity to leave their health plan during and after treatment. This study aimed to examine health care access duration among cancer survivors. Methods: Adult patients diagnosed with cancer between 11/1/2015 and 10/31/2016 were identified and followed until 11/1/2021. Control patients were identified as adults with no cancer diagnosis between 11/1/2015 and 11/1/2021. Patients with skin cancer were excluded due to limited care requirements. The primary outcomes were annual patient churn and median length of health plan enrollment duration. Propensity score (PS) matching was conducted between the groups utilizing patient demographics to balance comorbidities between groups. Comorbidity was described with the National Cancer Institute comorbidity index (NCI CI). Appropriate descriptive statistics were calculated and Cox proportional hazards (CPH) models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Overall, 3.2 million patients met the eligibility criteria, with 18% having cancer. Significant differences in the unmatched population were found, with the cancer group being older and having more comorbidities (p &lt; 0.001). Following PS matching, the differences in underlying demographic variables were minimal, despite being statistically significant. Unadjusted annual churn rate, defined as the percent of cancer patients leaving the health plan per year, averaged 25.44% overall, with the non-cancer group experiencing more churn most years (Table). Median length of health plan enrollment duration was 716 days (Interquartile range (IQR) = 819) overall, with the cancer group having less median duration than the non-cancer group in the matched analysis (713 [IQR 808] vs. 717 [IQR 822], p &lt; 0.001). After adjusting for the variables in the model, having a cancer diagnosis was associated with decreased risk of health plan disenrollment in multivariate CPH regression (HR 0.987 [95% CI 0.983 – 0.991]). Additional factors that increased the risk of disenrollment included: male gender (HR 1.011 [1.008-1.015]), Medicare eligibility (HR 1.290 [1.279-1.301]) and increasing NCI CI (1.124 [1.118-1.129]). Conclusions: Cancer patients experienced less churn from their health plan over a five-year follow-up. They were less at risk for disenrollment at any time than non-cancer patients when confounders are accounted for in multivariate modeling.[Table: see text]
The immediate patch test reaction to fragrance in patients with allergic contact dermatitis to fragrance: A prospective study
Authors: Nutchaya Amornruk, Noppachai Siranart, Prattana Sittiwattanawong, Patipark Kueanjinda, Suwimon Loplumlert, Jongkonnee Wongpiyabovorn
Journal: Journal of the American Academy of Dermatology (2022)
The timing of (salvage) radiotherapy influences the outcomes of bladder neck incision for bladder neck stenosis after robot-assisted radical prostatectomy
Authors: H. Veerman, A.N. Vis, M.J. Hagens, C. Tillier, T.A. Roeleveld, E. Wit, T.M. Sluis, P.J. Leeuwen, J.A. Nieuwenhuijzen, H.G. Van Der Poel
Journal: European Urology (2022)
Clinical significance of α2,3-sialylated prostate-specific antigen density and MRI for high-grade prostate cancer in biopsy-naïve men with elevated PSA level.
Authors: T. Yoneyama, H. Yamamoto, M. Sutoh Yoneyama, Y. Tobisawa, S. Hatakeyama, T. Narita, H. Kodama, M. Momota, H. Ito, S. Narita, F. Tsushima, K. Mitsuzuka, T. Yoneyama, Y. Hashimoto, W. Duivenvoorden, J.H. Pinthus, S. Kakeda, A. Ito, N. Tsuchiya, T. Habuchi, C. Ohyama
Journal: European Urology (2022)
Liquid-biopsy-derived glycoproteomic profiling as a novel means for noninvasive diagnosis of ovarian cancer.
Authors: Danie Serie, Kaitlynn Moser, Chad Pickering, Paul Aiyetan, Gege Xu, Rachel Rice, Prasanna Ramachandran, Klaus Lindpaintner
Journal: Journal of Clinical Oncology (2022)

e17604 Background: Ovarian cancer (OC) is the fifth- leading cause of cancer-related deaths among women, and the most lethal gynecological cancer. Currently available biomarkers, including CA-125 and HE4, show suboptimal diagnostic performance for differentiating among benign and malignant pelvic tumors, and the early recognition of OC. Differentiation of benign and malignant pelvic tumors is required for proper patient triaging and management, yet non-invasive methods remain a largely unmet medical need. Methods: We applied a novel platform for characterizing peripheral blood glycoproteomic biomarkers, combining liquid-chromatography/mass spectrometry (LC-MS) with artificial intelligence/neural networks (AI-NN) for the targeted quantification of serum protein glycosylation at intact glycopeptide level to analyze serum samples from 296 treatment-naïve women with histopathology-confirmed diagnosis of either benign (n = 151) or malignant (n = 145) tumors, and from 55 healthy control subjects, procured from a commercial biobank. Using data-dependent acquisition, a panel of 683 serum glycosylated and non-glycosylated peptides, representing 71 serum proteins, was interrogated. Samples were randomly divided into a training and a testing set for multivariable analysis. Data processing was performed using PB-Net, an in-house-developed high-throughput peak integration software. Raw data were normalized, processed by statistical analysis, and applied to machine learning models. Results: Comparison of glycopeptide abundances among patients with OC and benign pelvic tumors yielded 428 statistically significantly differentially expressed glycopeptides/peptides (at FDR &lt; 0.05). A subpanel of these markers used to generate a score for predicting OC yielded areas under the receiver-operating-characteristic of 0.955 and 0.894 in the training and testing sets, respectively. The predicted probability of malignancy increased with cancer stage, and probability distributions were similar across training and test sets. Applying the model to healthy subjects, not utilized in training, resulted in few misclassifications and a spread nearly equivalent to that of the benign tumor cases. This indicates the signature robustly predicts malignancy and severity of disease. Conclusions: Our novel approach exhibited impressive levels of accuracy for the noninvasive differentiation of benign and malignant pelvic masses, compared with existing biomarkers and algorithms, thereby demonstrating the utility of glycoprotein profiles as a powerful, noninvasive new diagnostic modality.
Assessment of early and late symptom toxicity in a real-world cancer treatment population using the PRO-CTCAE.
Authors: Aaron Galaznik, Peter Trask, William Dudley
Journal: Journal of Clinical Oncology (2022)

e18663 Background: The FDA’s Draft Guidance for Core Patient-Reported Outcomes (PROs) in Cancer Clinical Trials, recommends assessment of disease-related symptoms, symptomatic adverse events, overall side effect impact, physical function, and role function. This guidance also recommends that core PROs be assessed more frequently within the first few treatment cycles. The NCI’s PRO Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a system to evaluate symptomatic toxicity. The objective of this study is to assess the utility of frequent assessment early in treatment, using PRO-CTCAE measures for symptom monitoring. Methods: The patient cohort (n = 248) was derived from users of PROmpt ® , an application for remote patient reporting and provider symptom management, employed in routine care in 30+ integrated cancer treatment centers. Patients were enrolled (9/20-10/21) at treatment initiation. Baseline characteristics were assessed by survey and review of patient EMR records. PRO-CTCAE derived surveys of 14 core symptoms (pain, shortness-of-breath, nausea, diarrhea, sadness, anxiety, constipation, fever, neuropathy, insomnia, urinary problems, decreased appetite, fatigue and mouth sores) were administered weekly. Patients who completed surveys in weeks 1 – 3 AND weeks 9 – 11 were selected for analysis (n = 75), with weekly incidences calculated for these windows. Differences were tested using dependent measures T-test. Exploratory analysis of differences by gender, frailty status, and tumor type were also performed. Results: Overall cohort was predominantly female (86.7%), with mean age 59.6 yrs. Subjects with baseline multi-dimensional geriatric assessments (MGA), were 73% fit, 24.3% intermediate and 2.7% frail. The majority of symptoms (11 of 14) showed directional decline over time, with 6 trending towards significance (p &lt; / = 0.10). Increases, however, were statistically significant for neuropathy(p = 0.01) and directional for shortness-of-breath (p = 0.10) and mouth sores (p = 0.32). Conclusions: Findings support recommendations for frequent, early assessment, with weekly surveys showing higher symptom incidence for most items compared with later assessment. Observation of late symptom increases support continued, regular monitoring for timely management of emerging symptoms with continued treatment.